Education

BS, Preprofessional Studies, University of Notre Dame, 1980MD, Louisiana State Univerisity School of Medicine, 1984PhD, University of Alabama at Birmingham, 1995Internship and Residency, Internal Medicine, University of Texas Medical Branch, Galveston 1984-1987Chief Residency, Internal Medicine, University of Texas Medical Branch, Galveston 1987-1988Fellowship, Clinical Immunology and Rheumatology, University of Alabama at Birmingham, 1988-1991

Research Description and Potential Projects for Trainees

Our research program is focused on identification of genetic and non-genetic influences on rheumatoid arthritis susceptibility, severity, and treatment response, as delineated below.

Genetic and non-genetic influences on RA susceptibility and severity in African-Americans. Through the Consortium for the Longitudinal Evaluation of African-Americans with Early Rheumatoid Arthritis (CLEAR) Registry (NIH N01-AR-6-2278 - SL Bridges, Jr., PI), we are collecting clinical information and biological samples from African-Americans with RA. The current goals of CLEAR Registry are: 1) to complete our ongoing longitudinal evaluation of 400 African-Americans with early rheumatoid arthritis and enrollment of 200 healthy African-American controls matched for age-, sex-, and geographic location; and 2) to compile extensive demographic, socioeconomic, clinical, and radiographic data on 600 additional African-Americans with longstanding RA and 300 additional healthy African-American controls matched for age-, sex-, and geographic location. When complete, the CLEAR Registry will provide comprehensive clinical, socioeconomic, and radiographic data, as well as DNA, RNA, and serum on 1,000 patients and 500 controls for the scientific community.

We have a research project that is part of UAB's NIH-funded Multidisciplinary Clinical Research Center Project (2P60 AR048095 - Robert P. Kimberly, PI). This project, Predictors of Rheumatoid Arthritis Severity in African-Americans (SL Bridges, Jr., PI), has the following goals: 1) To identify differences in baseline gene expression profiles between African-American patients with RA and severe radiographic damage and those with no radiographic damage at 3 years' disease duration; 2) To identify differences in baseline serologic factors between African-American patients with RA and severe radiographic damage and those with no radiographic damage at 3 years' disease duration; and 3) To determine the relative contributions of baseline clinical, genetic, serologic, socioeconomic, environmental factors, and treatment on radiographic severity of RA in African-Americans at 3 years' disease duration.

In collaboration with investigators at the HudsonAlpha Institute of Biotechnology in Huntsville, Alabama, we will search for new genetic loci associated with RA in African-Americans through the project Genome-Wide Association Study in African-Americans with Rheumatoid Arthritis (NIH R01 AR057202-01 - SL Bridges, Jr., PI). The goals of this project are:; 1) to perform a genome-wide association study (GWAS) in 800 African-Americans with anti-CCP antibody positive RA and 800 controls to identify novel genetic associations; 2) to replicate these putative associations for susceptibility to CCP+ RA among African-Americans in independent set of 800 African-American CCP+ RA patients and 800 matched controls (which will be constituted by establishing the African-American Rheumatoid Arthritis Network (AARAN) and 3) To further characterize genetic regions associated with RA in African-Americans and to analyze genome-wide associations with radiographic severity; bone mineral density in early RA and healthy controls; and expression quantitative trait loci (eQTLs) of genes expressed in peripheral blood mononuclear cells, particularly those associated with radiographic severity.

Predictors of Response to Treatment in Rheumatoid Arthritis. As part of UAB's NIH-funded Multidisciplinary Clinical Research Center Project (see above), we have a project in collaboration with Drs. Donna Arnett and Beth Brown in the UAB Department of Epidemiology. This project, Genetic and Molecular Markers of Methotrexate Efficacy and Toxicity in Early RA (DK Arnett, PI), has the following goals: 1) To characterize the association between genetic variation and MTX efficacy, toxicity, and polyglutamate concentrations in early aggressive RA by genotyping haplotype-tagging SNPs or genetic variants reported to be related to methotrexate (MTX) efficacy, toxicity, and/or polyglutamination of MTX in 26 candidate genes in patients in the TEAR Trial (see below) 2) To conduct sophisticated analyses of single variants and haplotypes to assess the association between genetic variation and (a) efficacy (the longitudinal change in the DAS28 score from baseline to 24 weeks; (b) MTX polyglutamate concentrations measured using HPLC (high performance liquid chromatography), and (c) MTX toxicity during the first 24 weeks of the trial; and 3) To evaluate the role of non-genetic factors that mediate the effect of the genetic variants identified in Aim1 to influence efficacy, polyglutamate concentration, and toxicity.

The studies outlined in the project Genetic and Molecular Markers of Methotrexate Efficacy and Toxicity in Early RA are based on the Treatment of Early Aggressive Arthritis (TEAR) Trial led by Dr. Larry Moreland (now at the University of Pittsburgh) and Drs. Jeff Curtis, Stacey Cofield, and George Howard. The primary objective of this proposal is to evaluate the relative efficacy of two clinically important decisions as measured by the average DAS28 and two years after initiation of treatment: 1) To assess if it is better to intensively treat all early RA patients with multiple DMARDs, or reserve this treatment only to those who do not appropriately respond to MTX monotherapy and 2) To assess if the combination therapy of MTX plus etanercept is superior to MTX plus sulfasalazine plus hydroxychloroquine. Biological samples (DNA, RNA, serum/plasma) from patients enrolled in the TEAR Trial were collected as part of NIH R01 AR052658 (Predictors of Treatment Response in Early Aggressive RA - SL Bridges, Jr., PI), which ended in 2009.

Through the NIH Grand Opportunity grant Treatment Efficacy and Toxicity in Rheumatoid Arthritis Database and Repository (TETRAD) (NIH 1 RC2 AR058964 - SL Bridges, Jr., PI), we will pursue the following goals: 1) to create a collaborative network of leading academic investigators that will harmonize efforts to collect treatment response data and biologic samples in RA patients starting methotrexate (MTX) or biologic agents; 2) to implement a protocol recently constructed by leading academic rheumatologists, biostatisticians, geneticists, and immunologists to facilitate uniform data and specimen collection from RA patients starting treatment; 3) a. To perform a "proof of concept" study to determine the feasibility of this infrastructure by enrolling a small number of RA patients (10/year/site) beginning therapy;; 3) b. to utilize financial and in-kind contributions from the Arthritis Foundation and corporate partners to perform pilot projects to facilitate additional grant funding on mechanisms of treatment response in RA; and 4) to leverage the successes garnered in Aims 1-3 to stimulate collaborative efforts of federal funding agencies, voluntary health agencies, professional organizations and industry partners to enable creation of a large, sustainable database and repository to better understand the molecular basis of treatment and rapidly accelerate translational research in RA.